Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al., N. Engl. J. Med. 330, 811 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See, for example, Sjak-shie et al., Brain Res. 624, 295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons, upon administration of nicotine, has been reported by Rowell et al., J. Neurochem. 43, 1593 (1984); Rapier et al., J. Neurochem. 50, 1123 (1988); Sandor et al., Brain Res. 567, 313 (1991) and Vizi, Br. J. Pharmacol. 47, 765 (1973). Release of norepinephrine by neurons, upon administration of nicotine, has been reported by Hall et al., Biochem. Pharmacol. 21, 1829 (1972). Release of serotonin by neurons, upon administration of nicotine, has been reported by Hery et al., Arch. Int. Pharmacodyn. Ther. 296, 91 (1977). Release of glutamate by neurons, upon administration of nicotine, has been reported by Toth et al., Neurochem Res. 17, 265 (1992). Confirmatory reports and additional recent studies have included the modulation, in the central nervous system (CNS), of glutamate, nitric oxide, GABA, tachykinins, cytokines, and peptides (reviewed in Brioni et al., Adv. Pharmacol. 37, 153 (1997)). In addition, nicotine reportedly potentiates the pharmacological behavior of certain formulations used for the treatment of certain disorders. See, for example, Sanberg et al., Pharmacol. Biochem. & Behavior 46, 303 (1993); Harsing et al., J. Neurochem. 59, 48 (1993) and Hughes, Proceedings from Intl. Symp. Nic. S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed. See, for example, Decina et al., Biol. Psychiatry 28, 502 (1990); Wagner et al., Pharmacopsychiatry 21, 301 (1988); Pomerleau et al., Addictive Behaviors 9, 265 (1984); Onaivi et al., Life Sci. 54, 193 (1994); Tripathi et al., JPET 221, 91 (1982) and Hamon, Trends in Pharmacol. Res. 15, 36 (1994).
Various compounds that target nicotinic acetylcholine receptors (NAChRs) have been reported as being useful for treating a wide variety of conditions and disorders. See, for example, Williams et al., DN&P 7, 205 (1994); Arneric et al., CNS Drug Rev. 1, 1 (1995); Arneric et al., Exp. Opin. Invest. Drugs 5, 79 (1996); Bencherif et al., JPET 279, 1413 (1996); Lippiello et al., JPET 279, 1422 (1996); Damaj et al., J. Pharmacol. Exp. Ther. 291, 390 (1999); Chiari et al., Anesthesiology 91, 1447 (1999); Lavand'homme and Eisenbach, Anesthesiology 91, 1455 (1999); Holladay et al., J. Med. Chem. 40, 4169 (1997); Bannon et al., Science 279, 77 (1998); PCT WO 94/08992, PCT WO 96/31475, PCT WO 96/40682, and U.S. Pat. No. 5,583,140 to Bencherif et al., U.S. Pat. No. 5,597,919 to Dull et al., U.S. Pat. No. 5,604,231 to Smith et al., and U.S. Pat. No. 5,852,041 to Cosford et al. Nicotinic compounds are reported as being particularly useful for treating a wide variety of CNS disorders. Indeed, a wide variety of compounds have been reported to have therapeutic properties. See, for example, Bencherif and Schmitt, Current Drug Targets: CNS and Neurological Disorders 1, 349 (2002), Levin and Rezvani, Current Drug Targets: CNS and Neurological Disorders 1, 423 (2002), O'Neill et al., Current Drug Targets: CNS and Neurological Disorders 1, 399 (2002), U.S. Pat. No. 5,187,166 to Kikuchi et al., U.S. Pat. No. 5,672,601 to Cignarella, PCT WO 99/21834, PCT WO 97/40049, UK Patent Application GB 2295387, and European Patent Application 297,858.
CNS disorders are a type of neurological disorder. CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology. CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses, and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders. There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors). Several CNS disorders can be attributed to a deficiency of choline, dopamine, norepinephrine and/or serotonin. Relatively common CNS disorders include pre-senile dementia (early-onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), micro-infarct dementia, AIDS-related dementia, Creutzfeld-Jakob disease, Pick's disease, Parkinsonism including Parkinson's disease, Lewy body dementia, progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia, depression, obsessive-compulsive disorders and Tourette's syndrome.
The NAChRs characteristic of the CNS have been shown to occur in several subtypes, the most common of which are the α4β2 and α7 subtypes. See, for example, Schmitt, Current Med. Chem. 7, 749 (2000). Ligands that interact with the α7 NAChR subtype have been proposed to be useful in the treatment of schizophrenia. There are a decreased number of hippocampal NAChRs in postmortem brain tissue of schizophrenic individuals. Also, there is improved psychological effect in smoking versus non-smoking schizophrenic individuals. Nicotine improves sensory gating deficits in animals and schizophrenics. Blockade of the α7 NAChR subtype induces a gating deficit similar to that seen in schizophrenia. See, for example, Leonard et al., Schizophrenia Bulletin 22, 431 (1996). Biochemical, molecular, and genetic studies of sensory processing in individuals with the P50 auditory-evoked potential gating deficit suggest that the α7 NAChR subtype may function in an inhibitory neuronal pathway. See, for example, Freedman et al., Biological Psychiatry 38, 22 (1995).
More recently, α7 NAChRs have been proposed to be mediators of angiogenesis, as described by Heeschen et al., J. Clin. Invest. 100, 527 (2002), U.S. Pat. No. 6,417,207, U.S. Pat. No. 7,045,534, WO 01/08683 and WO 01/08684. In these studies, inhibition of the α7 subtype was shown to decrease inflammatory angiogenesis. Also, α7 NAChRs have been proposed as targets for controlling neurogenesis and tumor growth (Utsugisawa et al., Molecular Brain Research 106, 88 (2002) and U.S. Patent Application 2002/0016371). Finally, the role of the α7 subtype in cognition (Levin and Rezvani, Current Drug Targets: CNS and Neurological Disorders 1, 423 (2002)), neuroprotection (O'Neill et al., Current Drug Targets: CNS and Neurological Disorders 1, 399 (2002) and Jeyarasasingam et al., Neuroscience 109, 275 (2002)), and neuropathic pain (Xiao et al., Proc. Nat. Acad. Sci. 99, 8360 (2002)) has recently been recognized.
Various compounds have been reported to interact with α7 NAChRs and have been proposed as therapies on that basis. See, for instance, WO 99/62505, WO 99/03859, WO 97/30998, WO 01/36417, WO 02/15662, WO 02/16355, WO 02/16356, WO 02/16357, WO 02/16358, WO 02/17358, Stevens et al., Psychopharm. 136, 320 (1998), Dolle et al., J. Labelled Comp. Radiopharm. 44, 785 (2001) and Macor et al., Bioorg. Med. Chem. Lett. 11, 319 (2001) and references therein. Among these compounds, a common structural theme is that of a substituted tertiary bicyclic amine (e.g., quinuclidine). Similar quinuclidine compounds have also been reported to bind to muscarinic (U.S. Pat. No. 5,712,270, WO 02/00652 and WO 02/51841) as well as serotonergic receptors (U.S. Pat. No. 5,300,512 and U.S. Pat. No. 5,399,562).
European Patent Publication No. 491664A1 discloses 3,7-disubstituted indole derivatives for treating psychiatric disorders.
PCT Publication No. WO 93/15080 discloses azabicyclo compounds as calcium channel antagonists.
European Patent Publication No. 382687A2 discloses benzofused-N-containing heterocycle derivatives as muscarinic receptor blocking agents.
European Patent Publication No. 350130A2 discloses substituted 1,7-annelated 1H-indazoles as antagonists of “neuronal” 5-HT receptors.
U.S. Pat. No. 5,399,562 discloses indolones useful as 5-HT4 agonists or antagonists and 5-HT3 antagonists.
U.S. Pat. No. 5,300,512 discloses benzimidazole compounds useful in treating 5-HT4 and/or 5-HT3 mediated conditions.
PCT Publication No. WO 2009/046025 discloses substituted quinuclidine compounds useful in modulating α7 NAChR.
It would be desirable to provide useful methods for the prevention and treatment of nicotinic receptor-mediated conditions by administering a compound which mediates such conditions to an individual susceptible to or suffering from such a condition. It would be highly beneficial to provide individuals suffering from certain conditions (e.g., CNS diseases) with interruption of the symptoms of those conditions by the administration of a formulation containing an active ingredient having nicotinic pharmacology which has a beneficial effect (e.g., upon the functioning of the CNS), but does not provide any significant associated side effects. It would be highly desirable to provide a formulation incorporating a compound that interacts with NAChRs, such as those that have the potential to affect the functioning of the CNS. It would be highly desirable that such a compound, when employed in an amount sufficient to affect the functioning of the CNS, would not significantly affect those NAChR subtypes that have the potential to induce undesirable side effects (e.g., appreciable activity at cardiovascular and skeletal muscle receptor sites). In addition, it would be highly desirable to provide a formulation incorporating a compound which interacts with nicotinic receptors but not muscarinic receptors, as the latter are associated with side effects, such as hypersalivation, sweating, tremors, cardiovascular and gastrointestinal disturbances, related to the function of the parasympathetic nervous system (see Caulfield, Pharmacol. Ther. 58, 319 (1993) and Broadley and Kelly, Molecules 6, 142 (2001)). Furthermore, it would be highly desirable to provide formulations, which are selective for the α7 NAChR subtype, for the treatment of certain conditions (e.g., schizophrenia, cognitive disorders, neuropathic pain, and inflammation).